Project Summary: We propose a comprehensive integrated analysis of issues relating to anemia in the elderly. The overall aim of this proposal is to identify and characterize the cause and the severity of the anemia in several cohorts of elderly subjects;perform a comprehensive analysis of marrow hematopoeisis and erythropoeisis of the aged, both normal and anemic;and then determine the effect of correcting the anemia using a unique novel agent. Initially we will do a comprehensive hematologic evaluation of several cohorts of elerly anemic subjects, exploring the likely etiologies of the previously identified "unexplained anemia of the aged (UA)". Our underlying hypothesis is that many patients with this UA have a forme fruste of the anemia of chronic inflammation (ACI). In parallel, we will undertake to qualitatively and quantitatively analyze marrow hematopoeisis and erythropoeisis in non-anemic elderly subects at the cellular and molecular level, and compare these findings with marrow obtained from non-anemic young subjects. Then we will compare hematopoiesis/ erythropoiesis in the marrow of elderly non-anemic subjects with the marrow of elderly anemic subjects. As an integral part of this study we will seek to understand the underlying pathphysiologic events that underly the impaired erythropoeisis in specific subsets of anemic elderly, namely those with ACI and UA. And, finally, we will perform an intervention using an innovative agent which activates the entire cellular response to hypoxia in order to reverse the anemia in patients with ACI or UA. In doing so, we will correct the anemia per se without altering the probable underlying cause, and measure the effect on physical and cognitive performance. As part of the intervention, we will study marrow hematopoiesis in those who both respond and fail to respond to this intervention. Relevance: This project has substantial relevance for the large population of elderly patients with anemia, with respect to diagnosis;to understanding the basic mechanisms underlying the pathophysiology of the anemia;and to optimizing management. Current literature indicates that this population is underserved. Thus, we anticipate that a large proportion of participants will be able to derive an immediate benefit from participating in the study, and that the broader goals of improving understanding as to underlying etiology and optimal therapeutic strategies will lead to important medical advances.